Study: Immunosuppressive drugs for kidney transplants are suitable for xenotransplants
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Key takeaways:
- Immunosuppressive drugs prescribed to prevent kidney allograft rejection in humans can also be used with pig-to-human kidney transplants.
- Researchers found a complement inhibitor can help reduce rejection.
FDA-approved immunosuppressive drugs used to ward off rejection after a kidney transplant can be equally effective for pig-to-human transplants, particularly when a complement inhibitor is added to the regimen, a published study shows.
“I think this work is pivotal because it helps to define an optimal FDA-approved immunosuppressive regimen for a pig-to-human transplant that mimics what we use in human-to-human transplantation,” Jayme E. Locke, MD, professor of surgery at the University of Alabama at Birmingham (UAB) Marnix E. Heersink School of Medicine and an author on the study, told Healio. “It is significant because much of the work that has been done in pre-clinical, non-human primate xenotransplantation has leveraged immunosuppressive drug therapies that are not FDA approved and are not used in human-to-human transplantation,” Locke said. “So, to identify a regimen that we as transplant physicians and surgeons are already comfortable with and that works in a setting of pig-to-human transplant is important,” Locke said. “We are excited about how this is moving the field forward.”
Results presented in the study, published in the Journal of Clinical Investigation, represent the third set of xenotransplant findings from UAB surgeon scientists since 2022. In each case, the research team used the Parsons model, a preclinical human research model developed by UAB in a recipient experiencing brain death. The model is named for Jim Parsons, an organ donor from Alabama whose family donated his body to advance xenotransplant kidney research, according to a press release.
Allograft failure
UAB researchers have successfully transplanted genetically modified pig kidneys into a human recipient after brain death. However, they discovered an important finding, Locke told Healio, that can lead to rejection of the pig kidney called thrombotic microangiopathy (TMA).
“We do see this time to time in human allo- to allotransplantation,” Locke said. “When we see that early, it gives us pause that perhaps the body is reacting negatively to that new transplant, and that could be an early sign of rejection.
“We wanted to test this ... we were concerned that the end result of this TMA reflected a revved-up immune system called the complement system,” that can lead to rejection of the organ, Locke told Healio.
A complement inhibitor can be used to counteract the immune system “forming a membrane attack complex — a microscopic battering ram that breaks through a cell’s defenses, ultimately causing organ failure,” according to the release.
The membrane attack complex (MAC) “essentially sets up like a little drill on the surface of a cell and it drills holes in the cell,” Locke told Healio. “If you drill holes in the cell, it weakens and it dies. If you kill enough cells, then the tissue dies. If you kill enough tissue, then the organ dies. The complement inhibitor prevents the formation of this drill on the surface of the cell. It’s like creating a force shield around the kidney.”
The complement inhibitor is already an FDA-approved regimen for patients with a rare kidney disease known as atypical hemolytic uremic syndrome.
Results
In the study, the complement inhibitor was used in two of three donor patients, or decedents, aged 53 to 65 years who received bilateral native nephrectomies followed by xenotransplantation with 10 gene-edited pig kidneys. The first recipient received standard immunosuppression.
“There was no evidence of hyperacute rejection in any decedent,” the authors wrote. “Decedents 2 and 3 received anti-C5 monoclonal antibody therapy (eculizumab) 24 hours prior to (1,200 mg) and 24 hours after (900 mg) xenotransplantation.”
While the biopsies of the pig kidneys were histologically normal in the first decedent after being transplanted on the first day, the new organs began to show some signs of rejection the day after transplant, Locke said. The two decedents receiving the complement inhibitor did not show any signs of rejection.
“While complement activation in the setting of both brain death and xenotransplantation is difficult to decipher, C5 inhibition may be beneficial in preventing TMA in pig-to-human xenotransplantation,” Locke and colleagues wrote. “However, decedent 1 native kidneys had no evidence of complement activation, yet after xenotransplantation MAC deposition and TMA progressed rapidly, suggesting an immune response to the xenograft rather than brain death physiology.”
The study findings are “great news,” Locke said in the release. “We now know that we have an FDA-approved immunosuppression regimen already available. It’s a regimen that we know the patient can tolerate, and it is a treatment transplant doctors are familiar with and already know how to use.
“This is another critical piece that I hope will soon lead to FDA clearance for a phase I clinical trial in living humans.”
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